中国临床试验注册中心 - 世界卫生组织国际临床试验注册平台一级注册机构

注册号： Registration number：	ChiCTR2500098554
最近更新日期： Date of Last Refreshed on：	2025-03-10 17:47:32
注册时间： Date of Registration：	2025-03-10 00:00:00
注册号状态：	预注册
Registration Status：	Prospective registration
注册题目：	NKG2D CAR-NK联合PD-1单抗治疗甲状腺未分化癌（ATC）临床探索性研究
Public title：	Clinical exploratory study of NKG2D CAR-NK combined with PD-1 monoclonal antibody in the treatment of anaplastic thyroid cancer (ATC)
注册题目简写：	NKG2D CAR-NK联合PD-1单抗治疗ATC的临床研究
English Acronym：	Clinical study of NKG2D CAR-NK combined with PD-1 monoclonal antibody in the treatment of ATC
研究课题的正式科学名称：	NKG2D CAR-NK 联合PD-1 单抗治疗甲状腺未分化癌(ATC)的前瞻性临床研究
Scientific title：	Prospective clinical study of NKG2D CAR-NK combined with PD-1 monoclonal antibody in the treatment of anaplastic thyroid carcinoma (ATC)
研究课题代号(代码)： Study subject ID：
在二级注册机构或其它机构的注册号： The registration number of the Partner Registry or other register：

申请注册联系人：	冯冬冬	研究负责人：	葛明华
Applicant：	Dongdong Feng	Study leader：	Minghua Ge
申请注册联系人电话： Applicant telephone：	+86 187 6718 5235	研究负责人电话： Study leader's telephone：	+86 136 0581 3782
申请注册联系人传真： Applicant Fax：		研究负责人传真： Study leader's fax：
申请注册联系人电子邮件： Applicant E-mail：	fddjaky@163.com	研究负责人电子邮件： Study leader's E-mail：	geminghua@hmc.edu.cn
申请单位网址(自愿提供)： Applicant website(voluntary supply)：		研究负责人网址(自愿提供)： Study leader's website(voluntary supply)：
申请注册联系人通讯地址：	浙江省杭州市拱墅区上塘路158号浙江省人民医院	研究负责人通讯地址：	浙江省杭州市拱墅区上塘路158号浙江省人民医院
Applicant address：	Zhejiang Provincial People's Hospital, No.158 Shangtang Road, Gongshu District, Hangzhou City, Zhejiang Province, China.	Study leader's address：	Zhejiang Provincial People's Hospital, No.158 Shangtang Road, Gongshu District, Hangzhou City, Zhejiang Province, China.
申请注册联系人邮政编码： Applicant postcode：	310014	研究负责人邮政编码： Study leader's postcode：	310014
申请人所在单位：	浙江省人民医院
Applicant's institution：	Zhejiang Provincial People’s Hospital
研究负责人所在单位：	浙江省人民医院
Affiliation of the Leader：	Zhejiang Provincial People’s Hospital

是否获伦理委员会批准：	是
Approved by ethic committee：	Yes
伦理委员会批件文号： Approved No. of ethic committee：	浙人医伦审2024研第(218)号	伦理委员会批件附件： Approved file of Ethical Committee：	查看附件View
批准本研究的伦理委员会名称：	浙江省人民医院伦理委员会
Name of the ethic committee：	Ethics Committee of Zhejiang Provincial People's Hospital
伦理委员会批准日期： Date of approved by ethic committee：	2024-09-20 00:00:00
伦理委员会联系人：	李青青
Contact Name of the ethic committee：	Qingqing Li
伦理委员会联系地址：	浙江省杭州市拱墅区上塘路158号，浙江省人民医院
Contact Address of the ethic committee：	Zhejiang Provincial People's Hospital, No.158 Shangtang Road, Gongshu District, Hangzhou City, Zhejiang Province, China.
伦理委员会联系人电话： Contact phone of the ethic committee：	+86 571 8589 3643	伦理委员会联系人邮箱： Contact email of the ethic committee：

研究实施负责（组长）单位：

浙江省人民医院

Primary sponsor：

Zhejiang Provincial People's Hospital

研究实施负责（组长）单位地址：

浙江省杭州市拱墅区上塘路158号

Primary sponsor's address：

158 Shangtang Road, Gongshu District, Hangzhou City, Zhejiang Province, China

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：	中国	省(直辖市)：	浙江省	市(区县)：	杭州市
Country：	China	Province：	Zhejiang Province	City：	Hangzhou City
单位(医院)：	浙江省人民医院	具体地址：	浙江省杭州市拱墅区上塘路158号
Institution hospital：	Zhejiang Provincial People's Hospital	Address：	Zhejiang Provincial People's Hospital, 158 Shangtang Road, Gongshu District, Hangzhou City, Zhejiang Province, China

经费或物资来源：

浙江省“尖兵”“领雁”研发攻关计划(2024C03157)

Source(s) of funding：

the Key Research and Development Program of Zhejiang Province(2024C03157)

研究疾病：

甲状腺未分化癌

Target disease：

Anaplastic thyroid cancer

研究疾病代码：

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

I期+II期

Study phase：

1-2

研究设计：

单臂

Study design：

Single arm

研究目的：

1.主要目标：对甲状腺未分化癌患者进行CAR-NK 免疫细胞联合PD-1 单抗联合治疗，观察和评估患者的安全性、耐受性。 2.次要目标： 1) 根据剂量限制毒性和临床反应情况包括可能的副作用情况，确定最大耐受剂量(MTD) 和/或推荐的II 期剂量（RP2D）。 2) 评估药效学（PD）生物标志物与临床疗效的相关性； 3) 评估对标准治疗失败的甲状腺未分化癌（ATC）患者的初步抗肿瘤疗效。采用客观缓解率（ORR）、缓解持续时间（DOR）、疾病控制率（DCR）和无进展生存期（PFS）描述初步抗肿瘤活性。 4) 与治疗相关的不良反应事件发生率。 3.探索性目的： 1) 评估NKG2D CAR-NK 联合PD-1 单抗治疗时受试者免疫状态的变化。 2) 评估NKG2D CAR-NK 细胞治疗时药代动力学特征。

Objectives of Study：

1. Primary Objective: To observe and evaluate the safety and tolerability of CAR-NK cell therapy combined with PD-1 monoclonal antibody in patients with anaplastic thyroid carcinoma (ATC). 2. Secondary Objectives: (1)To determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) based on dose-limiting toxicities (DLTs) and clinical responses, including potential adverse effects. (2)To assess the correlation between pharmacodynamic (PD) biomarkers and clinical efficacy. (3)To evaluate the preliminary anti-tumor efficacy in ATC patients who have failed standard treatments. Preliminary anti-tumor activity will be described using objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). (4)To assess the incidence of treatment-related adverse events. 3. Exploratory Objectives: (1)To evaluate changes in the immune status of subjects during treatment with NKG2D CAR-NK cells combined with PD-1 monoclonal antibody. (2)To assess the pharmacokinetic characteristics of NKG2D CAR-NK cell therapy.

药物成份或治疗方案详述：

Description for medicine or protocol of treatment in detail：

纳入标准：

Inclusion criteria

1.Age between 18 and 75 years (inclusive), both males and females are eligible.

2.Histologically confirmed anaplastic thyroid cancer; either not completely resectable by surgery or recurrent after surgery, with BRAF(-) on genetic testing, or BRAF(+) but refusing or unable to use BRAF-related targeted drugs, or progression after treatment with BRAF-related targeted drugs.

3.ECOG performance status score of 0-1, able to tolerate comprehensive treatments including surgery, chemotherapy, radiotherapy, and immunotherapy. Agree to provide tumor tissue samples and peripheral blood for testing and preparation of CAR-NK cells.

4.Able to cooperate in providing tumor tissue samples and peripheral blood for laboratory tests related to the research.

5.Expected survival period of the subject is >=12 weeks.

6.The subject must have at least one target lesion that can be stably evaluated according to RECIST V.1.1 criteria via CT, MRI, or PET-CT. The target lesion must have measurable dimensions (tumor lesion with a long diameter >=10 mm on CT scan, lymph node lesion with a short diameter >=15 mm on CT scan, with a scan thickness not exceeding 5 mm).

7.The subject has adequate organ and bone marrow function. Laboratory screening must meet the following criteria, with all laboratory test results within the specified stable ranges and without ongoing supportive treatment.
a) Blood tests: WBC >= 1.5×10^9/L; PLT >=60×10^9/L; Hb >=8.0g/dL; LYM>=0.4×10^9/L;
b) Blood biochemistry: Serum creatinine <=1.5 × ULN, if serum creatinine >1.5 × ULN, creatinine clearance rate must be >50mL/min (calculated by Cockcroft-Gault formula); Serum total bilirubin <=1.5×ULN, ALT <=2 ×ULN, AST <= 2 ×ULN (for patients with liver metastasis or liver cancer, ALT <=5×ULN, AST <=5×ULN).
c) Amylase and lipase <= 1.5 × ULN;
d) Urinalysis: Urine protein < 2+.

8.Fertility status: Female patients of childbearing potential or male patients with female partners of childbearing potential must be willing to use effective contraception from the time of signing the informed consent until 6 months after the last cell infusion (women of childbearing potential include premenopausal women and women within 2 years of menopause).

9.The subject must sign and date a written informed consent form.

10.The subject must voluntarily and be able to comply with the planned treatment, laboratory tests, follow-up, and other study requirements.

排除标准：

1. 妊娠期和哺乳期无法人工喂养的女性。 2. 已知的人类免疫缺陷病毒（HIV）感染史；急性或慢性活动性乙型肝炎（HBsAg 阳性）；急性或慢性活动性丙型肝炎（HCV 抗体阳性）。梅毒抗体阳性；EB 病毒DNA 定量＞200 copies；巨细胞病毒（CMV）感染（IgM 阳性）。 3. 处于活动期或临床控制不佳的严重感染。 4. 目前存在需要治疗的心脏病或经过研究者判断控制不佳的高血压（定义为经规范化降压药治疗后收缩压>=140 mmHg 和/或舒张压＞90 mmHg）。 5. 存在以下任何心脏临床症状或疾病： a) 半年内发生过心肌梗死且相关专业医生认为心梗无法控制或不可预防； b) 静息状态心电图检查QTc＞450ms(男性)或者QTc＞470ms（女性）且拒绝预防性调控或监测心脏电传导； c) 静息状态心电图检查发现有重要临床意义的异常（如心率、传导、形态特征等异常）或完全性左束支传导阻滞或三级心脏传导阻滞或二级心脏传导阻滞或者PR 间期＞250ms，且拒绝起搏器植入等预防性干预措施； d) 存在增加QTc 延长、心率异常风险的因素，如心力衰竭、低钾血症、先天性长QT综合征、长QT 综合征家族史或有40 岁以下直系亲属不明原因猝死、或有延长间期伴随用药，且经相关专业医生评估认为属于心跳骤停或恶性心律失常高风险的患者。 6. 凝血功能异常（INR＞1.5× ULN），具有出血倾向或正在接受溶栓或常规抗凝治疗（如华法林或肝素），患者需要长期抗血小板治疗（阿司匹林，剂量＞300mg/day；氯吡格雷，剂量＞75mg/day），且无法切换为低分子肝素抗凝的患者。 7. 在治疗期间内需要使用皮质类固醇或其他免疫抑制药物进行全身治疗的受试者。 8. 治疗前血氧饱和度<=90%（指脉氧检测，且指端无病变；否则改为血气分析），经治疗后无法改善。 9. 治疗前4 周内接受过相当于＞15mg/天泼尼松的全身性类固醇药物，吸入性类固醇除外。 10. 现患或有中枢神经系统疾病史的患者，如癫痫发作、脑血管缺血/出血、痴呆、小脑疾病或任何伴累及中枢神经系统的自身免疫性疾病；具有临床症状的中枢神经系统转移或脑膜转移，或有其他证据表明患者中枢神经系统转移或脑膜转移灶尚未控制，经研究者判断不适合入组。 11. 现患有间质性肺病或肺炎，肺纤维化，急性肺部疾病等。 12. 既往曾接受过NK 或CAR-NK 免疫细胞治疗。 13. 治疗前4 周内接受过抗PD-1/PD-L1 单克隆抗体治疗。 14. 既往接受过其他基因治疗的受试者。 15. 有严重精神障碍性疾病的受试者且不具备民事行为能力的患者。 16. 过去1 月内曾参加其他的临床研究且未过洗脱期。 17. 研究者评估受试者不能或不愿意遵守研究方案的要求。 18. 受试者因各种原因退出研究，不能再次参加研究。

Exclusion criteria：

1.Women who are pregnant, or breastfeeding but unable to use artificial feeding. 2.Known history of human immunodeficiency virus (HIV) infection; acute or chronic active hepatitis B (HBsAg positive); acute or chronic active hepatitis C (HCV antibody positive). Syphilis antibody positive; EB virus DNA quantification >200 copies; cytomegalovirus (CMV) infection (IgM positive). 3.Severe infections that are active or clinically poorly controlled. 4.Current presence of heart disease requiring treatment or hypertension judged by the investigator as poorly controlled (defined as systolic blood pressure >=140 mmHg and/or diastolic blood pressure >90 mmHg after standardized antihypertensive treatment). 5.Presence of any of the following cardiac clinical symptoms or diseases: a) Myocardial infarction within the past six months, and the relevant specialist considers the infarction uncontrollable or unpreventable; b) Resting electrocardiogram showing QTc >450ms (male) or QTc >470ms (female) and refusal of preventive regulation or monitoring of cardiac electrical conduction; c) Resting electrocardiogram showing clinically significant abnormalities (e.g., heart rate, conduction, morphological features, etc.) or complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval >250ms, and refusal of preventive interventions such as pacemaker implantation; d) Factors increasing the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death in first-degree relatives under 40 years old, or concomitant use of drugs that prolong the interval, and assessed by the relevant specialist as high risk for cardiac arrest or malignant arrhythmia. 6.Abnormal coagulation function (INR >1.5 × ULN), bleeding tendency, or undergoing thrombolytic or routine anticoagulation therapy (e.g., warfarin or heparin), patients requiring long-term antiplatelet therapy (aspirin, dose >300mg/day; clopidogrel, dose >75mg/day), and unable to switch to low molecular weight heparin anticoagulation. 7.Subjects requiring systemic treatment with corticosteroids or other immunosuppressive drugs during the treatment period. 8.Pre-treatment oxygen saturation <=90% (pulse oximetry, with no lesions at the fingertip; otherwise, arterial blood gas analysis is required), and no improvement after treatment. 9.Systemic steroid drugs equivalent to >15mg/day prednisone within 4 weeks before treatment, excluding inhaled steroids. 10.Patients with current or history of central nervous system diseases, such as seizures, cerebral ischemia/hemorrhage, dementia, cerebellar diseases, or any autoimmune diseases involving the central nervous system; symptomatic central nervous system metastases or meningeal metastases, or other evidence indicating uncontrolled central nervous system or meningeal metastases, judged by the investigator as unsuitable for enrollment. 11.Current interstitial lung disease, pneumonia, pulmonary fibrosis, acute lung diseases, etc. 12.Previous treatment with NK or CAR-NK immune cell therapy. 13.Treatment with anti-PD-1/PD-L1 monoclonal antibodies within 4 weeks before treatment. 14.Subjects who have previously received other gene therapies. 15.Subjects with severe psychiatric disorders and lacking civil capacity. 16.Participation in other clinical studies within the past month without completing the washout period. 17.Investigator assessment that the subject cannot or is unwilling to comply with the study protocol requirements. 18.Subjects who have withdrawn from the study for various reasons and cannot re-participate in the study.

研究实施时间：

Study execute time：

从 From 2025-03-10 00:00:00至 To 2029-03-01 00:00:00

征募观察对象时间：

Recruiting time：

从 From 2025-03-10 00:00:00 至 To 2029-03-01 00:00:00

干预措施：

Interventions：

组别：	实验组	样本量：	30
Group：	Experimental group	Sample size：	30
干预措施：	NKG2D CAR-NK联合PD-1单抗	干预措施代码：
Intervention：	NKG2D CAR-NK cells with PD-1 monoclonal antibody	Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：	中国	省(直辖市)：	浙江省	市(区县)：	杭州
Country：	China	Province：	Zhejiang Province	City：	Hangzhou City
单位(医院)：	浙江省人民医院	单位级别：	三甲
Institution hospital：	Zhejiang Provincial People's Hospital	Level of the institution：	Tertiary A

测量指标：

Outcomes：

指标中文名：	28天耐受性	指标类型：	主要指标
Outcome：	Tolerance at day 28	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	28天安全性	指标类型：	主要指标
Outcome：	Tolerance at day 28	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	NKG2D CAR-NK细胞拷贝数	指标类型：	次要指标
Outcome：	NKG2D CAR-NK cell copy number	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	NKG2D CAR-NK存活时间	指标类型：	次要指标
Outcome：	NKG2D CAR-NK survival time	Type：	Secondary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	肿瘤客观缓解率	指标类型：	附加指标
Outcome：	Tumor objective response rate	Type：	Additional indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	疾病控制率	指标类型：	主要指标
Outcome：	Objective tumor response rate	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	缓解持续时间	指标类型：	主要指标
Outcome：	Duration of remission	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	无进展生存期	指标类型：	主要指标
Outcome：	Progression free survival	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	总生存期	指标类型：	主要指标
Outcome：	Overall survival	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

指标中文名：	细胞因子	指标类型：	主要指标
Outcome：	Cytokine	Type：	Primary indicator
测量时间点：		测量方法：
Measure time point of outcome：		Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：	血液	组织：
Sample Name：	Blood	Tissue：
人体标本去向	使用后销毁	说明
Fate of sample：	Destruction after use	Note：

标本中文名：	甲状腺未分化癌组织	组织：
Sample Name：	Anaplastic thyroid cancer	Tissue：
人体标本去向	使用后保存	说明
Fate of sample：	Preservation after use	Note：

征募研究对象情况：

Recruiting status：

正在进行

Recruiting

年龄范围：

Participant age：

最小 Min age	18	岁 years
最大 Max age	75	岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

单臂研究，无需随机。

Randomization Procedure (please state who generates the random number sequence and by what method)：

Single arm.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：
Blinding：
试验完成后的统计结果（上传文件）：	点击下载
Calculated Results after the Study Completed(upload file)：	download

是否共享原始数据： IPD sharing	是Yes
共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：	2030年12月31日后，可通过邮箱fddjaky@163.com咨询共享数据事宜。
The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：	After 31 December 2030, information about data can be obtained by cennecting fddjaky@163.com.
数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：	CRF表
Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：	Case report form
数据与安全监察委员会： Data and Safety Monitoring Committee：	暂未确定/Not yet
注册人： Name of Registration：	2025-03-10 17:47:28